Drug Combinations to Preempt Resistance in AML

2020 Emerging Leader Award

Jeffrey Tyner, PhD, Oregon Health and Science University

Jeffrey Tyner, PhD

Dr. Tyner is researching new drug combinations that can help avoid relapse in acute myeloid leukemia (AML) patients who have been treated with targeted therapeutic agents. Although response rates with targeted therapies are promising (ranging from 30% to 80%), most AML patients will relapse in less than one year. Researchers in the Tyner laboratory are using CRISPR/Cas9 genetic screens to uncover mechanisms of sensitivity or resistance to a panel of different drug combinations and to predict which combinations are most likely to have longer-lasting anti-cancer activity. Dr. Tyner attended Grinnell College and Washington University in St. Louis and is currently a Professor at the Knight Cancer Institute, Oregon Health & Science University. Dr. Tyner’s research is focused on drug combinations to enhance therapeutic efficacy and circumvent drug resistance.

published research

Eide CA, Kurtz SE, Kaempf A, Long N, Agarwal A, Tognon CE, Mori M, Druker BJ, Chang BH, Danilov AV, Tyner JW. Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia. Leukemia. 2020.

Zhang H, Nakauchi Y, Köhnke T, Stafford M, Bottomly D, Thomas R, Wilmot B, McWeeney SK, Majeti R, Tyner JW. Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia. Nat Cancer. 2020.

Joshi SK, Keck JM, Eide CA, Bottomly D, Traer E, Tyner JW, McWeeney SK, Tognon CE, Druker BJ. ERBB2/HER2 mutations are transforming and therapeutically targetable in leukemia. Leukemia. 2020.

Damnernsawad A, Bottomly D, Kurtz SE, Eide CA, McWeeney SK, Tyner JW, Nechiporuk T. Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia. Haematologica. 2020.

Tognon CE, Sears RC, Mills GB, Gray JW, Tyner JW. Ex Vivo Analysis of Primary Tumor Specimens for Evaluation of Cancer Therapeutics. Annu Rev Cancer Biol. 2021.

Romine KA, Nechiporuk T, Bottomly D, Jeng S, McWeeney SK, Kaempf A, Corces MR, Majeti R, Tyner JW. Monocytic differentiation and AHR signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia. Blood Cancer Discov. 2021.

White BS, Khan SA, Mason MJ, Ammad-Ud-Din M, Potdar S, Malani D, Kuusanmäki H, Druker BJ, Heckman C, Kallioniemi O, Kurtz SE, Porkka K, Tognon CE, Tyner JW, Aittokallio T, Wennerberg K, Guinney J. Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia. NPJ Precis Oncol. 2021.

Joshi SK, Nechiporuk T, Bottomly D, Piehowski PD, Reisz JA, Pittsenbarger J, Kaempf A, Gosline SJC, Wang YT, Hansen JR, Gritsenko MA, Hutchinson C, Weitz KK, Moon J, Cendali F, Fillmore TL, Tsai CF, Schepmoes AA, Shi T, Arshad OA, McDermott JE, Babur O, Watanabe-Smith K, Demir E, D’Alessandro A, Liu T, Tognon CE, Tyner JW, McWeeney SK, Rodland KD, Druker BJ, Traer E. The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance. Cancer Cell. 2021.

Shomali W, Damnernsawad A, Theparee T, Sampson D, Morrow Q, Yang F, Fernandez-Pol S, Press R, Zehnder J, Tyner JW, Gotlib J. A novel activating JAK1 mutation in chronic eosinophilic leukemia. Blood Adv. 2021.

Giacopelli B, Wang M, Cleary A, Wu YZ, Schultz AR, Schmutz M, Blachly JS, Eisfeld AK, Mundy-Bosse B, Vosberg S, Greif PA, Claus R, Bullinger L, Garzon R, Coombes KR, Bloomfield CD, Druker BJ, Tyner JW, Byrd JC, Oakes CC. DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia. Genome Res. 2021.

Thieme E, Liu T, Bruss N, Roleder C, Lam V, Wang X, Nechiporuk T, Shouse G, Danilova OV, Bottomly D, McWeeney SK, Tyner JW, Kurtz SE, Danilov AV. Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma. Cell Death Dis. 2022.

Kurtz SE, Eide CA, Kaempf A, Long N, Bottomly D, Nikolova O, Druker BJ, McWeeney SK, Chang BH, Tyner JW, Agarwal A. Associating Drug Sensitivity with Differentiation Status Identifies Effective Combinations for Acute Myeloid Leukemia. Blood Adv. 2022.

Rice WG, Howell SB, Zhang H, Rastgoo N, Local A, Kurtz SE, Lo P, Bottomly D, Wilmot B, McWeeney SK, Druker BJ, Tyner JW. Luxeptinib (CG-806) targets FLT3 and clusters of kinases operative in acute myeloid leukemia. Mol Cancer Ther. 2022.

Bottomly D, Long N, Schultz AR, Kurtz SE, Tognon CE, Johnson K, Abel M, Agarwal A, Avaylon S, Benton E, Blucher A, Borate U, Braun TP, Brown J, Bryant J, Burke R, Carlos A, Chang BH, Cho HJ, Christy S, Coblentz C, Cohen AM, d’Almeida A, Cook R, Danilov A, Dao KT, Degnin M, Dibb J, Eide CA, English I, Hagler S, Harrelson H, Henson R, Ho H, Joshi SK, Junio B, Kaempf A, Kosaka Y, Laderas T, Lawhead M, Lee H, Leonard JT, Lin C, Lind EF, Liu SQ, Lo P, Loriaux MM, Luty S, Maxson JE, Macey T, Martinez J, Minnier J, Monteblanco A, Mori M, Morrow Q, Nelson D, Ramsdill J, Rofelty A, Rogers A, Romine KA, Ryabinin P, Saultz JN, Sampson DA, Savage SL, Schuff R, Searles R, Smith RL, Spurgeon SE, Sweeney T, Swords RT, Thapa A, Thiel-Klare K, Traer E, Wagner J, Wilmot B, Wolf J, Wu G, Yates A, Zhang H, Cogle CR, Collins RH, Deininger MW, Hourigan CS, Jordan CT, Lin TL, Martinez ME, Pallapati RR, Pollyea DA, Pomicter AD, Watts JM, Weir SJ, Druker BJ, McWeeney SK, Tyner JW. Integrative analysis of drug response and clinical outcome in acute myeloid leukemia. Cancer Cell. 2022.

Rosenberg MW, Savage SL, Eide CA, Reister Schultz A, Cook RJ, Press RD, Rempfer C, Eickelberg G, Wilmot B, McWeeney SK, Tyner JW, Druker BJ, Tognon CE. Comprehensive molecular characterization of a rare case of Philadelphia chromosome-positive acute myeloid leukemia. Cold Spring Harb Mol Case Stud. 2022.

Savoy L, Long N, Lee H, Chen R, Allen B, Lin HY, Tognon C, V Malhotra S, Tyner JW, Zhang H. CDK12/13 dual inhibitors are potential therapeutics for acute myeloid leukemia. Br J Haematol. 2023.

Romine KA, Bottomly D, Yashar W, Long N, Viehdorfer M, McWeeney SK, Tyner JW. Immune cell proportions correlate with clinicogenomic features and ex vivo drug responses in acute myeloid leukemia. Front Oncol. 2023.